TY - JOUR A1 - Tuchscherr, Lorena A1 - Bischoff, Markus A1 - Lattar, Santiago M. A1 - Noto Llana, Mariangeles A1 - Pförtner, Henrike A1 - Niemann, Silke A1 - Geraci, Jennifer A1 - Van de Vyver, Hélène A1 - Fraunholz, Martin J. A1 - Cheung, Ambrose L. A1 - Herrmann, Mathias A1 - Völker, Uwe A1 - Sordelli, Daniel O. A1 - Peters, Georg A1 - Loeffler, Bettina T1 - Sigma factor SigB is crucial to mediate Staphylococcus aureus adaptation during chronic infections JF - PLoS Pathogens N2 - Staphylococcus aureus is a major human pathogen that causes a range of infections from acute invasive to chronic and difficult-to-treat. Infection strategies associated with persisting S. aureus infections are bacterial host cell invasion and the bacterial ability to dynamically change phenotypes from the aggressive wild-type to small colony variants (SCVs), which are adapted for intracellular long-term persistence. The underlying mechanisms of the bacterial switching and adaptation mechanisms appear to be very dynamic, but are largely unknown. Here, we analyzed the role and the crosstalk of the global S. aureus regulators agr, sarA and SigB by generating single, double and triple mutants, and testing them with proteome analysis and in different in vitro and in vivo infection models. We were able to demonstrate that SigB is the crucial factor for adaptation in chronic infections. During acute infection, the bacteria require the simultaneous action of the agr and sarA loci to defend against invading immune cells by causing inflammation and cytotoxicity and to escape from phagosomes in their host cells that enable them to settle an infection at high bacterial density. To persist intracellularly the bacteria subsequently need to silence agr and sarA. Indeed agr and sarA deletion mutants expressed a much lower number of virulence factors and could persist at high numbers intracellularly. SigB plays a crucial function to promote bacterial intracellular persistence. In fact, \(\Delta\)sigB-mutants did not generate SCVs and were completely cleared by the host cells within a few days. In this study we identified SigB as an essential factor that enables the bacteria to switch from the highly aggressive phenotype that settles an acute infection to a silent SCV-phenotype that allows for long-term intracellular persistence. Consequently, the SigB-operon represents a possible target to develop preventive and therapeutic strategies against chronic and therapy-refractory infections. KW - gene regulator agr KW - endothelial cells KW - modulates virulence KW - death pathway sar locus KW - factor B KW - small-colony variants KW - alpha-toxin KW - epithelial cells KW - in vitro Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143419 VL - 11 IS - 4 ER - TY - JOUR A1 - Tsamadou, Chrysanthi A1 - Fürst, Daniel A1 - Vucinic, Vladan A1 - Bunjes, Donald A1 - Neuchel, Christine A1 - Mytilineos, Daphne A1 - Gramatzki, Martin A1 - Arnold, Renate A1 - Wagner, Eva Maria A1 - Einsele, Hermann A1 - Müller, Carlheinz A1 - Schrezenmeier, Hubert A1 - Mytilineos, Joannis T1 - Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients JF - Haematologica N2 - The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs. 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48–0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs. 18%, P=0.005; HR=0.40, CI 95%=0.22–0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post–transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs. KW - medicine KW - acute leukemia (AL) KW - hematopoietic stem cell transplantation (HSCT) KW - human leukocyte antigen-E (HLA-E) KW - HLA-E matching KW - HSTC outcome Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173325 VL - 102 IS - 11 ER - TY - JOUR A1 - Bencurova, Elena A1 - Shityakov, Sergey A1 - Schaack, Dominik A1 - Kaltdorf, Martin A1 - Sarukhanyan, Edita A1 - Hilgarth, Alexander A1 - Rath, Christin A1 - Montenegro, Sergio A1 - Roth, Günter A1 - Lopez, Daniel A1 - Dandekar, Thomas T1 - Nanocellulose composites as smart devices with chassis, light-directed DNA Storage, engineered electronic properties, and chip integration JF - Frontiers in Bioengineering and Biotechnology N2 - The rapid development of green and sustainable materials opens up new possibilities in the field of applied research. Such materials include nanocellulose composites that can integrate many components into composites and provide a good chassis for smart devices. In our study, we evaluate four approaches for turning a nanocellulose composite into an information storage or processing device: 1) nanocellulose can be a suitable carrier material and protect information stored in DNA. 2) Nucleotide-processing enzymes (polymerase and exonuclease) can be controlled by light after fusing them with light-gating domains; nucleotide substrate specificity can be changed by mutation or pH change (read-in and read-out of the information). 3) Semiconductors and electronic capabilities can be achieved: we show that nanocellulose is rendered electronic by iodine treatment replacing silicon including microstructures. Nanocellulose semiconductor properties are measured, and the resulting potential including single-electron transistors (SET) and their properties are modeled. Electric current can also be transported by DNA through G-quadruplex DNA molecules; these as well as classical silicon semiconductors can easily be integrated into the nanocellulose composite. 4) To elaborate upon miniaturization and integration for a smart nanocellulose chip device, we demonstrate pH-sensitive dyes in nanocellulose, nanopore creation, and kinase micropatterning on bacterial membranes as well as digital PCR micro-wells. Future application potential includes nano-3D printing and fast molecular processors (e.g., SETs) integrated with DNA storage and conventional electronics. This would also lead to environment-friendly nanocellulose chips for information processing as well as smart nanocellulose composites for biomedical applications and nano-factories. KW - nanocellulose KW - DNA storage KW - light-gated proteins KW - single-electron transistors KW - protein chip Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283033 SN - 2296-4185 VL - 10 ER - TY - JOUR A1 - Schneider, Verena A1 - Kruse, Daniel A1 - Bernardelli de Mattos, Ives A1 - Zöphel, Saskia A1 - Tiltmann, Kendra-Kathrin A1 - Reigl, Amelie A1 - Khan, Sarah A1 - Funk, Martin A1 - Bodenschatz, Karl A1 - Groeber-Becker, Florian T1 - A 3D in vitro model for burn wounds: monitoring of regeneration on the epidermal level JF - Biomedicines N2 - Burns affect millions every year and a model to mimic the pathophysiology of such injuries in detail is required to better understand regeneration. The current gold standard for studying burn wounds are animal models, which are under criticism due to ethical considerations and a limited predictiveness. Here, we present a three-dimensional burn model, based on an open-source model, to monitor wound healing on the epidermal level. Skin equivalents were burned, using a preheated metal cylinder. The healing process was monitored regarding histomorphology, metabolic changes, inflammatory response and reepithelialization for 14 days. During this time, the wound size decreased from 25% to 5% of the model area and the inflammatory response (IL-1β, IL-6 and IL-8) showed a comparable course to wounding and healing in vivo. Additionally, the topical application of 5% dexpanthenol enhanced tissue morphology and the number of proliferative keratinocytes in the newly formed epidermis, but did not influence the overall reepithelialization rate. In summary, the model showed a comparable healing process to in vivo, and thus, offers the opportunity to better understand the physiology of thermal burn wound healing on the keratinocyte level. KW - skin models KW - open-source epidermis KW - wound model KW - impedance spectroscopy KW - wound physiology KW - burn wound Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246068 SN - 2227-9059 VL - 9 IS - 9 ER - TY - JOUR A1 - Lüke, Florian A1 - Haller, Florian A1 - Utpatel, Kirsten A1 - Krebs, Markus A1 - Meidenbauer, Norbert A1 - Scheiter, Alexander A1 - Spoerl, Silvia A1 - Heudobler, Daniel A1 - Sparrer, Daniela A1 - Kaiser, Ulrich A1 - Keil, Felix A1 - Schubart, Christoph A1 - Tögel, Lars A1 - Einhell, Sabine A1 - Dietmaier, Wolfgang A1 - Huss, Ralf A1 - Dintner, Sebastian A1 - Sommer, Sebastian A1 - Jordan, Frank A1 - Goebeler, Maria-Elisabeth A1 - Metz, Michaela A1 - Haake, Diana A1 - Scheytt, Mithun A1 - Gerhard-Hartmann, Elena A1 - Maurus, Katja A1 - Brändlein, Stephanie A1 - Rosenwald, Andreas A1 - Hartmann, Arndt A1 - Märkl, Bruno A1 - Einsele, Hermann A1 - Mackensen, Andreas A1 - Herr, Wolfgang A1 - Kunzmann, Volker A1 - Bargou, Ralf A1 - Beckmann, Matthias W. A1 - Pukrop, Tobias A1 - Trepel, Martin A1 - Evert, Matthias A1 - Claus, Rainer A1 - Kerscher, Alexander T1 - Identification of disparities in personalized cancer care — a joint approach of the German WERA consortium JF - Cancers N2 - (1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy. KW - precision oncology KW - MTB KW - patient access KW - cancer care KW - outreach KW - real world data KW - outcomes research Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290311 SN - 2072-6694 VL - 14 IS - 20 ER - TY - JOUR A1 - Bellinger, Daniel A1 - Wehrmann, Kristin A1 - Rohde, Anna A1 - Schuppert, Maria A1 - Störk, Stefan A1 - Flohr-Jost, Michael A1 - Gall, Dominik A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Herrmann, Martin J. A1 - Erhardt-Lehmann, Angelika T1 - The application of virtual reality exposure versus relaxation training in music performance anxiety: a randomized controlled study JF - BMC Psychiatry N2 - Background Performance anxiety is the most frequently reported anxiety disorder among professional musicians. Typical symptoms are - on a physical level - the consequences of an increase in sympathetic tone with cardiac stress, such as acceleration of heartbeat, increase in blood pressure, increased respiratory rate and tremor up to nausea or flush reactions. These symptoms can cause emotional distress, a reduced musical and artistical performance up to an impaired functioning. While anxiety disorders are preferably treated using cognitive-behavioral therapy with exposure, this approach is rather difficult for treating music performance anxiety since the presence of a public or professional jury is required and not easily available. The use of virtual reality (VR) could therefore display an alternative. So far, no therapy studies on music performance anxiety applying virtual reality exposure therapy have investigated the therapy outcome including cardiovascular changes as outcome parameters. Methods This mono-center, prospective, randomized and controlled clinical trial has a pre-post design with a follow-up period of 6 months. 46 professional and semi-professional musicians will be recruited and allocated randomly to an VR exposure group or a control group receiving progressive muscle relaxation training. Both groups will be treated over 4 single sessions. Music performance anxiety will be diagnosed based on a clinical interview using ICD-10 and DSM-5 criteria for specific phobia or social anxiety. A behavioral assessment test is conducted three times (pre, post, follow-up) in VR through an audition in a concert hall. Primary outcomes are the changes in music performance anxiety measured by the German Bühnenangstfragebogen and the cardiovascular reactivity reflected by heart rate variability (HRV). Secondary outcomes are changes in blood pressure, stress parameters such as cortisol in the blood and saliva, neuropeptides, and DNA-methylation. Discussion The trial investigates the effect of VR exposure in musicians with performance anxiety compared to a relaxation technique on anxiety symptoms and corresponding cardiovascular parameters. We expect a reduction of anxiety but also a consecutive improvement of HRV with cardiovascular protective effects. Trial registration This study was registered on clinicaltrials.gov. (ClinicalTrials.gov Number: NCT05735860) KW - music performance anxiety KW - virtual reality exposure therapy KW - progressive muscle relaxation KW - heart rate variability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357833 VL - 23 ER - TY - JOUR A1 - Tütüncü, Serdar A1 - Olma, Manuel A1 - Kunze, Claudia A1 - Dietzel, Joanna A1 - Schurig, Johannes A1 - Fiessler, Cornelia A1 - Malsch, Carolin A1 - Haas, Tobias Eberhard A1 - Dimitrijeski, Boris A1 - Doehner, Wolfram A1 - Hagemann, Georg A1 - Hamilton, Frank A1 - Honermann, Martin A1 - Jungehulsing, Gerhard Jan A1 - Kauert, Andreas A1 - Koennecke, Hans-Christian A1 - Mackert, Bruno-Marcel A1 - Nabavi, Darius A1 - Nolte, Christian H. A1 - Reis, Joschua Mirko A1 - Schmehl, Ingo A1 - Sparenberg, Paul A1 - Stingele, Robert A1 - Völzke, Enrico A1 - Waldschmidt, Carolin A1 - Zeise-Wehry, Daniel A1 - Heuschmann, Peter U. A1 - Endress, Matthias A1 - Haeusler, Karl Georg T1 - Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry JF - Journal of Neurology N2 - Aims We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. Methods The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. Results At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05-7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04-10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24-9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01-0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08-2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28-2.84, P < 0.01]. Conclusion At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. KW - NOAC KW - ischemic stroke KW - atrial fibrillation KW - under-dosing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266969 SN - 1432-1459 VL - 269 IS - 1 ER - TY - JOUR A1 - Diefenhardt, Markus A1 - Martin, Daniel A1 - Ludmir, Ethan B. A1 - Fleischmann, Maximilian A1 - Hofheinz, Ralf-Dieter A1 - Ghadimi, Michael A1 - Kosmala, Rebekka A1 - Polat, Bülent A1 - Friede, Tim A1 - Minsky, Bruce D. A1 - Rödel, Claus A1 - Fokas, Emmanouil T1 - Development and validation of a predictive model for toxicity of neoadjuvant chemoradiotherapy in rectal cancer in the CAO/ARO/AIO-04 phase III trial JF - Cancers N2 - Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3–4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3–4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making. KW - rectal cancer KW - toxicity KW - neoadjuvant KW - chemoradiotherapy KW - risk score Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288081 SN - 2072-6694 VL - 14 IS - 18 ER - TY - JOUR A1 - Kämmerer, Peer W. A1 - Tribius, Silke A1 - Cohrs, Lena A1 - Engler, Gabriel A1 - Ettl, Tobias A1 - Freier, Kolja A1 - Frerich, Bernhard A1 - Ghanaati, Shahram A1 - Gosau, Martin A1 - Haim, Dominik A1 - Hartmann, Stefan A1 - Heiland, Max A1 - Herbst, Manuel A1 - Hoefert, Sebastian A1 - Hoffmann, Jürgen A1 - Hölzle, Frank A1 - Howaldt, Hans-Peter A1 - Kreutzer, Kilian A1 - Leonhardt, Henry A1 - Lutz, Rainer A1 - Moergel, Maximilian A1 - Modabber, Ali A1 - Neff, Andreas A1 - Pietzka, Sebastian A1 - Rau, Andrea A1 - Reichert, Torsten E. A1 - Smeets, Ralf A1 - Sproll, Christoph A1 - Steller, Daniel A1 - Wiltfang, Jörg A1 - Wolff, Klaus-Dietrich A1 - Kronfeld, Kai A1 - Al-Nawas, Bilal T1 - Adjuvant radiotherapy in patients with squamous cell carcinoma of the oral cavity or oropharynx and solitary ipsilateral lymph node metastasis (pN1) — a prospective multicentric cohort study JF - Cancers N2 - (1) Background: Evaluation of impact of adjuvant radiation therapy (RT) in patients with oral squamous cell carcinoma of the oral cavity/oropharynx (OSCC) of up to 4 cm (pT1/pT2) and solitary ipsilateral lymph node metastasis (pN1). A non-irradiated group with clinical follow-up was chosen for control, and survival and quality of life (QL) were compared; (2) Methods: This prospective multicentric comprehensive cohort study included patients with resected OSCC (pT1/pT2, pN1, and cM0) who were allocated into adjuvant radiation therapy (RT) or observation. The primary endpoint was overall survival. Secondary endpoints were progression-free survival and QL after surgery; (3) Results: Out of 27 centers, 209 patients were enrolled with a median follow-up of 3.4 years. An amount of 137 patients were in the observation arm, and 72 received adjuvant irradiation. Overall survival did not differ between groups (hazard ratio (HR) 0.98 [0.55–1.73], p = 0.94). There were fewer neck metastases (HR 0.34 [0.15–0.77]; p = 0.01), as well as fewer local recurrences (HR 0.41 [0.19–0.89]; p = 0.02) under adjuvant RT. For QL, irradiated patients showed higher values for the symptom scale pain after 0.5, two, and three years (all p < 0.05). After six months and three years, irradiated patients reported higher symptom burdens (impaired swallowing, speech, as well as teeth-related problems (all p < 0.05)). Patients in the RT group had significantly more problems with mouth opening after six months, one, and two years (p < 0.05); (4) Conclusions: Adjuvant RT in patients with early SCC of the oral cavity and oropharynx does not seem to influence overall survival, but it positively affects progression-free survival. However, irradiated patients report a significantly decreased QL up to three years after therapy compared to the observation group. KW - oral squamous cell carcinoma KW - oropharyngeal carcinoma KW - surgery KW - resection KW - radiotherapy KW - survival KW - progression-free survival KW - quality of life KW - prospective KW - multicentric KW - lymph node KW - pN1 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311024 SN - 2072-6694 VL - 15 IS - 6 ER - TY - JOUR A1 - Stebani, Jannik A1 - Blaimer, Martin A1 - Zabler, Simon A1 - Neun, Tilmann A1 - Pelt, Daniël M. A1 - Rak, Kristen T1 - Towards fully automated inner ear analysis with deep-learning-based joint segmentation and landmark detection framework JF - Scientific Reports N2 - Automated analysis of the inner ear anatomy in radiological data instead of time-consuming manual assessment is a worthwhile goal that could facilitate preoperative planning and clinical research. We propose a framework encompassing joint semantic segmentation of the inner ear and anatomical landmark detection of helicotrema, oval and round window. A fully automated pipeline with a single, dual-headed volumetric 3D U-Net was implemented, trained and evaluated using manually labeled in-house datasets from cadaveric specimen (N = 43) and clinical practice (N = 9). The model robustness was further evaluated on three independent open-source datasets (N = 23 + 7 + 17 scans) consisting of cadaveric specimen scans. For the in-house datasets, Dice scores of 0.97 and 0.94, intersection-over-union scores of 0.94 and 0.89 and average Hausdorf distances of 0.065 and 0.14 voxel units were achieved. The landmark localization task was performed automatically with an average localization error of 3.3 and 5.2 voxel units. A robust, albeit reduced performance could be attained for the catalogue of three open-source datasets. Results of the ablation studies with 43 mono-parametric variations of the basal architecture and training protocol provided task-optimal parameters for both categories. Ablation studies against single-task variants of the basal architecture showed a clear performance beneft of coupling landmark localization with segmentation and a dataset-dependent performance impact on segmentation ability. KW - anatomy KW - bone imaging KW - diagnosis KW - medical imaging KW - software KW - three-dimensional imaging KW - tomography Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357411 VL - 13 ER - TY - JOUR A1 - Odorfer, Thorsten M. A1 - Homola, György A. A1 - Reich, Martin M. A1 - Volkmann, Jens A1 - Zeller, Daniel T1 - Increased finger-tapping related cerebellar activation in cervical dystonia, enhanced by transcranial stimulation: an indicator of compensation? JF - Frontiers in Neurology N2 - Background: Cervical dystonia is a movement disorder causing abnormal postures and movements of the head. While the exact pathophysiology of cervical dystonia has not yet been fully elucidated, a growing body of evidence points to the cerebellum as an important node. Methods: Here, we examined the impact of cerebellar interference by transcranial magnetic stimulation on finger-tapping related brain activation and neurophysiological measures of cortical excitability and inhibition in cervical dystonia and controls. Bilateral continuous theta-burst stimulation was used to modulate cerebellar cortical excitability in 16 patients and matched healthy controls. In a functional magnetic resonance imaging arm, data were acquired during simple finger tapping before and after cerebellar stimulation. In a neurophysiological arm, assessment comprised motor-evoked potentials amplitude and cortical silent period duration. Theta-burst stimulation over the dorsal premotor cortex and sham stimulation (neurophysiological arm only) served as control conditions. Results: At baseline, finger tapping was associated with increased activation in the ipsilateral cerebellum in patients compared to controls. Following cerebellar theta-burst stimulation, this pattern was even more pronounced, along with an additional movement-related activation in the contralateral somatosensory region and angular gyrus. Baseline motor-evoked potential amplitudes were higher and cortical silent period duration shorter in patients compared to controls. After cerebellar theta-burst stimulation, cortical silent period duration increased significantly in dystonia patients. Conclusion: We conclude that in cervical dystonia, finger movements—though clinically non-dystonic—are associated with increased activation of the lateral cerebellum, possibly pointing to general motor disorganization, which remains subclinical in most body regions. Enhancement of this activation together with an increase of silent period duration by cerebellar continuous theta-burst stimulation may indicate predominant disinhibitory effects on Purkinje cells, eventually resulting in an inhibition of cerebello-thalamocortical circuits. KW - cervical dystonia KW - functional MRI KW - cortical excitability KW - transcranial magnetic simulation (TMS) KW - continuous theta burst stimulation (cTBS) KW - motor-evoked potentials (MEP) KW - cortical silent period Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196249 SN - 1664-2295 VL - 10 IS - 231 ER - TY - JOUR A1 - Rauch, Florian A1 - Endres, Peter A1 - Friedrich, Alexandra A1 - Sieh, Daniel A1 - Hähnel, Martin A1 - Krummenacher, Ivo A1 - Braunschweig, Holger A1 - Finze, Maik A1 - Ji, Lei A1 - Marder, Todd B. T1 - An Iterative Divergent Approach to Conjugated Starburst Borane Dendrimers JF - Chemistry – A European Journal N2 - Using a new divergent approach, conjugated triarylborane dendrimers were synthesized up to the 2nd generation. The synthetic strategy consists of three steps: 1) functionalization, via iridium catalyzed C−H borylation; 2) activation, via fluorination of the generated boronate ester with K[HF\(_{2}\)] or [N(nBu\(_{4}\))][HF\(_{2}\)]; and 3) expansion, via reaction of the trifluoroborate salts with aryl Grignard reagents. The concept was also shown to be viable for a convergent approach. All but one of the conjugated borane dendrimers exhibit multiple, distinct and reversible reduction potentials, making them potentially interesting materials for applications in molecular accumulators. Based on their photophysical properties, the 1st generation dendrimers exhibit good conjugation over the whole system. However, the conjugation does not increase further upon expansion to the 2nd generation, but the molar extinction coefficients increase linearly with the number of triarylborane subunits, suggesting a potential application as photonic antennas. KW - density functional calculations KW - electron storage KW - luminescence KW - redox KW - triarylborane Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218345 VL - 26 IS - 57 SP - 12951 EP - 12963 ER - TY - JOUR A1 - Schiele, Miriam A. A1 - Ziegler, Christiane A1 - Kollert, Leonie A1 - Katzorke, Andrea A1 - Schartner, Christoph A1 - Busch, Yasmin A1 - Gromer, Daniel A1 - Reif, Andreas A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Herrmann, Martin J. A1 - Domschke, Katharina T1 - Plasticity of Functional MAOA Gene Methylation in Acrophobia JF - International Journal of Neuropsychopharmacology N2 - Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction. KW - monoamine oxidase A KW - anxiety KW - extinction KW - epigenetics KW - DNA methylation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228571 VL - 21 IS - 9 ER - TY - JOUR A1 - Doghman-Bouguerra, Mabrouka A1 - Finetti, Pascal A1 - Durand, Nelly A1 - Parise, Ivy Zortéa S. A1 - Sbiera, Silviu A1 - Cantini, Giulia A1 - Canu, Letizia A1 - Hescot, Ségolène A1 - Figueiredo, Mirna M. O. A1 - Komechen, Heloisa A1 - Sbiera, Iuliu A1 - Nesi, Gabriella A1 - Paci, Angelo A1 - Al Ghuzlan, Abir A1 - Birnbaum, Daniel A1 - Baudin, Eric A1 - Luconi, Michaela A1 - Fassnacht, Martin A1 - Figueiredo, Bonald C. A1 - Bertucci, François A1 - Lalli, Enzo T1 - Cancer-testis antigen FATE1 expression in adrenocortical tumors is associated with a pervasive autoimmune response and is a marker of malignancy in adult, but not children, ACC JF - Cancers N2 - The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy. KW - adrenocortical carcinoma KW - cancer-testis antigens KW - autoantibodies KW - immune response Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203211 SN - 2072-6694 VL - 12 IS - 3 ER - TY - JOUR A1 - Schischlevskij, Pavel A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Stendel, Claudia A1 - Müschen, Lars H. A1 - Osmanovic, Alma A1 - Binz, Camilla A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives JF - Brain Sciences N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = −0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required. KW - amyotrophic lateral sclerosis (ALS) KW - informal caregiving KW - caregiver burden KW - functional status KW - decreasing autonomy KW - depression KW - anxiety KW - health-related quality of life KW - socioeconomic status KW - psychological support Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240981 SN - 2076-3425 VL - 11 IS - 6 ER - TY - JOUR A1 - Tuca, Alexandru-Cristian A1 - Bernardelli de Mattos, Ives A1 - Funk, Martin A1 - Winter, Raimund A1 - Palackic, Alen A1 - Groeber-Becker, Florian A1 - Kruse, Daniel A1 - Kukla, Fabian A1 - Lemarchand, Thomas A1 - Kamolz, Lars-Peter T1 - Orchestrating the dermal/epidermal tissue ratio during wound healing by controlling the moisture content JF - Biomedicines N2 - A balanced and moist wound environment and surface increases the effect of various growth factors, cytokines, and chemokines, stimulating cell growth and wound healing. Considering this fact, we tested in vitro and in vivo water evaporation rates from the cellulose dressing epicite\(^{hydro}\) when combined with different secondary dressings as well as the resulting wound healing efficacy in a porcine donor site model. The aim of this study was to evaluate how the different rates of water evaporation affected wound healing efficacy. To this end, epicite\(^{hydro}\) primary dressing, in combination with different secondary dressing materials (cotton gauze, JELONET\(^◊\), AQUACEL\(^®\) Extra\(^™\), and OPSITE\(^◊\) Flexifix), was placed on 3 × 3 cm-sized dermatome wounds with a depth of 1.2 mm on the flanks of domestic pigs. The healing process was analyzed histologically and quantified by morphometry. High water evaporation rates by using the correct secondary dressing, such as cotton gauze, favored a better re-epithelialization in comparison with the low water evaporation resulting from an occlusive secondary dressing, which favored the formation of a new and intact dermal tissue that nearly fully replaced all the dermis that was removed during wounding. This newly available evidence may be of great benefit to clinical wound management. KW - bacterial cellulose dressing KW - secondary wound dressing KW - moisture balance KW - wound healing KW - in vivo experiments Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275115 SN - 2227-9059 VL - 10 IS - 6 ER - TY - JOUR A1 - Vogel, Patrick A1 - Markert, Jonathan A1 - Rückert, Martin A. A1 - Herz, Stefan A1 - Keßler, Benedikt A1 - Dremel, Kilian A1 - Althoff, Daniel A1 - Weber, Matthias A1 - Buzug, Thorsten M. A1 - Bley, Thorsten A. A1 - Kullmann, Walter H. A1 - Hanke, Randolf A1 - Zabler, Simon A1 - Behr, Volker C. T1 - Magnetic Particle Imaging meets computed tomography: first simultaneous imaging JF - Scientific Reports N2 - Magnetic Particle Imaging (MPI) is a promising new tomographic modality for fast as well as three-dimensional visualization of magnetic material. For anatomical or structural information an additional imaging modality such as computed tomography (CT) is required. In this paper, the first hybrid MPI-CT scanner for multimodal imaging providing simultaneous data acquisition is presented. KW - Applied physics KW - Biomedical engineering KW - Imaging techniques Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202501 VL - 9 ER - TY - JOUR A1 - Kaiser, Anna A1 - Aggensteiner, Pascal-M. A1 - Holtmann, Martin A1 - Fallgatter, Andreas A1 - Romanos, Marcel A1 - Abenova, Karina A1 - Alm, Barbara A1 - Becker, Katja A1 - Döpfner, Manfred A1 - Ethofer, Thomas A1 - Freitag, Christine M. A1 - Geissler, Julia A1 - Hebebrand, Johannes A1 - Huss, Michael A1 - Jans, Thomas A1 - Jendreizik, Lea Teresa A1 - Ketter, Johanna A1 - Legenbauer, Tanja A1 - Philipsen, Alexandra A1 - Poustka, Luise A1 - Renner, Tobias A1 - Retz, Wolfgang A1 - Rösler, Michael A1 - Thome, Johannes A1 - Uebel-von Sandersleben, Henrik A1 - von Wirth, Elena A1 - Zinnow, Toivo A1 - Hohmann, Sarah A1 - Millenet, Sabina A1 - Holz, Nathalie E. A1 - Banaschewski, Tobias A1 - Brandeis, Daniel T1 - EEG data quality: determinants and impact in a multicenter study of children, adolescents, and adults with attention-deficit/hyperactivity disorder (ADHD) JF - Brain Sciences N2 - Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (n\(_{total}\) = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value. KW - electroencephalography (EEG) KW - data quality KW - attention-deficit/hyperactivity disorder (ADHD) KW - artifacts KW - multicenter study Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228788 SN - 2076-3425 VL - 11 IS - 2 ER - TY - JOUR A1 - Geissler, Julia A1 - Jans, Thomas A1 - Banaschewski, Tobias A1 - Becker, Katja A1 - Renner, Tobias A1 - Brandeis, Daniel A1 - Döpfner, Manfred A1 - Dose, Christina A1 - Hautmann, Christopher A1 - Holtmann, Martin A1 - Jenkner, Carolin A1 - Millenet, Sabina A1 - Romanos, Marcel T1 - Individualised short-term therapy for adolescents impaired by attention-deficit/hyperactivity disorder despite previous routine care treatment (ESCAadol)-Study protocol of a randomised controlled trial within the consortium ESCAlife JF - Trials N2 - Background: Despite the high persistence rate of attention-deficit/hyperactivity disorder (ADHD) throughout the lifespan, there is a considerable gap in knowledge regarding effective treatment strategies for adolescents with ADHD. This group in particular often shows substantial psychosocial impairment, low compliance and insufficient response to psychopharmacological interventions. Effective and feasible treatments should further consider the developmental shift in ADHD symptoms, comorbidity and psychosocial adversity as well as family dysfunction. Thus, individualised interventions for adolescent ADHD should comprise a multimodal treatment strategy. The randomised controlled ESCAadol study addresses the needs of this patient group and compares the outcome of short-term cognitive behavioural therapy with parent-based telephone-assisted self-help. Methods/design: In step 1, 160 adolescents aged 12 to 17 years with a diagnosis of ADHD will undergo a treatment as usual (TAU) observation phase of 1 month. In step 2, those still severely affected are randomised to the intervention group with an Individualised Modular Treatment Programme (IMTP) or a telephone-assisted self-help programme for parents (TASH) as an active control condition. The IMTP was specifically designed for the needs of adolescent ADHD. It comprises 10 sessions of individual cognitive behavioural therapy with the adolescents and/or the parents, for which participants choose three out of 10 available focus modules (e.g. organisational skills and planning, emotion regulation, problem solving and stress management, dysfunctional family communication). TASH combines a bibliotherapeutic component with 10 counselling sessions for the parents via telephone. Primary outcome is the change in ADHD symptoms in a clinician-rated diagnostic interview. Outcomes are assessed at inclusion into the study, after the TAU phase, after the intervention phase and after a further 12-week follow-up period. The primary statistical analysis will be by intention-to-treat, using linear regression models. Additionally, we will analyse psychometric and biological predictors and moderators of treatment response. Discussion: ESCAadol compares two short-term non-pharmacological interventions as cost-efficient and feasible treatment options for adolescent ADHD, addressing the specific needs and obstacles to treatment success in this group. We aim to contribute to personalised medicine for adolescent ADHD intended to be implemented in routine clinical care. KW - ADHD KW - adolescents KW - attention-deficit/hyperactivity disorder KW - behaviour therapy KW - RCT KW - individualised modular treatment programme KW - telephone-assisted self-help Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176061 VL - 19 IS - 254 ER - TY - JOUR A1 - Peseschkian, Tara A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Büchner, Boriana A1 - Weiland, Ulrike A1 - Schönfelder, Erik A1 - Heinrich, Felix A1 - Osmanovic, Alma A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - A nation-wide, multi-center study on the quality of life of ALS patients in Germany JF - Brain Sciences N2 - Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care. KW - Amyotrophic Lateral Sclerosis (ALS) KW - Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) KW - ALS treatment KW - “bulbar-onset” ALS (bALS) KW - “limb-onset” ALS (lALS) KW - EuroQol Five Dimension Five Level Scale (EQ-5D-5L) KW - health-related quality of life (HRQoL) KW - quality of life (QoL) KW - symptom-specific treatment KW - assistive devices Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234147 SN - 2076-3425 VL - 11 IS - 3 ER - TY - JOUR A1 - Vedder, Daniel A1 - Lens, Luc A1 - Martin, Claudia A. A1 - Pellikka, Petri A1 - Adhikari, Hari A1 - Heiskanen, Janne A1 - Engler, Jan O. A1 - Sarmento Cabral, Juliano T1 - Hybridization may aid evolutionary rescue of an endangered East African passerine JF - Evolutionary Applications N2 - Abstract Introgressive hybridization is a process that enables gene flow across species barriers through the backcrossing of hybrids into a parent population. This may make genetic material, potentially including relevant environmental adaptations, rapidly available in a gene pool. Consequently, it has been postulated to be an important mechanism for enabling evolutionary rescue, that is the recovery of threatened populations through rapid evolutionary adaptation to novel environments. However, predicting the likelihood of such evolutionary rescue for individual species remains challenging. Here, we use the example of Zosterops silvanus, an endangered East African highland bird species suffering from severe habitat loss and fragmentation, to investigate whether hybridization with its congener Zosterops flavilateralis might enable evolutionary rescue of its Taita Hills population. To do so, we employ an empirically parameterized individual‐based model to simulate the species' behaviour, physiology and genetics. We test the population's response to different assumptions of mating behaviour and multiple scenarios of habitat change. We show that as long as hybridization does take place, evolutionary rescue of Z. silvanus is likely. Intermediate hybridization rates enable the greatest long‐term population growth, due to trade‐offs between adaptive and maladaptive introgressed alleles. Habitat change did not have a strong effect on population growth rates, as Z. silvanus is a strong disperser and landscape configuration is therefore not the limiting factor for hybridization. Our results show that targeted gene flow may be a promising avenue to help accelerate the adaptation of endangered species to novel environments, and demonstrate how to combine empirical research and mechanistic modelling to deliver species‐specific predictions for conservation planning. KW - evolutionary rescue KW - habitat change KW - individual‐based model KW - introgressive hybridization KW - Taita Hills KW - Zosterops silvanus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287264 VL - 15 IS - 7 ER - TY - JOUR A1 - López, Cristina A1 - Kleinheinz, Kortine A1 - Aukema, Sietse M. A1 - Rohde, Marius A1 - Bernhart, Stephan H. A1 - Hübschmann, Daniel A1 - Wagener, Rabea A1 - Toprak, Umut H. A1 - Raimondi, Francesco A1 - Kreuz, Markus A1 - Waszak, Sebastian M. A1 - Huang, Zhiqin A1 - Sieverling, Lina A1 - Paramasivam, Nagarajan A1 - Seufert, Julian A1 - Sungalee, Stephanie A1 - Russell, Robert B. A1 - Bausinger, Julia A1 - Kretzmer, Helene A1 - Ammerpohl, Ole A1 - Bergmann, Anke K. A1 - Binder, Hans A1 - Borkhardt, Arndt A1 - Brors, Benedikt A1 - Claviez, Alexander A1 - Doose, Gero A1 - Feuerbach, Lars A1 - Haake, Andrea A1 - Hansmann, Martin-Leo A1 - Hoell, Jessica A1 - Hummel, Michael A1 - Korbel, Jan O. A1 - Lawerenz, Chris A1 - Lenze, Dido A1 - Radlwimmer, Bernhard A1 - Richter, Julia A1 - Rosenstiel, Philip A1 - Rosenwald, Andreas A1 - Schilhabel, Markus B. A1 - Stein, Harald A1 - Stilgenbauer, Stephan A1 - Stadler, Peter F. A1 - Szczepanowski, Monika A1 - Weniger, Marc A. A1 - Zapatka, Marc A1 - Eils, Roland A1 - Lichter, Peter A1 - Loeffler, Markus A1 - Möller, Peter A1 - Trümper, Lorenz A1 - Klapper, Wolfram A1 - Hoffmann, Steve A1 - Küppers, Ralf A1 - Burkhardt, Birgit A1 - Schlesner, Matthias A1 - Siebert, Reiner T1 - Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma JF - Nature Communications N2 - Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing. KW - cancer genomics KW - lymphocytes KW - lymphoid tissues KW - oncology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237281 VL - 10 ER - TY - JOUR A1 - Godel, Tim A1 - Pham, Mirko A1 - Kele, Henrich A1 - Kronlage, Moritz A1 - Schwarz, Daniel A1 - Brunée, Merle A1 - Heiland, Sabine A1 - Bendszus, Martin A1 - Bäumer, Philipp T1 - Diffusion tensor imaging in anterior interosseous nerve syndrome – functional MR Neurography on a fascicular level JF - NeuroImage: Clinical N2 - Purpose By applying diffusor tensor imaging (DTI) in patients with anterior interosseous nerve syndrome (AINS), this proof of principle study aims to quantify the extent of structural damage of a peripheral nerve at the anatomical level of individual fascicles. Methods In this institutional review board approved prospective study 13 patients with spontaneous AINS were examined at 3 Tesla including a transversal T2-weighted turbo-spin-echo and a spin-echo echo-planar-imaging pulse sequence of the upper arm level. Calculations of quantitative DTI parameters including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for median nerve lesion and non-lesion fascicles as well as ulnar and radial nerve were obtained. DTI values were compared to each other and to a previously published dataset of 58 healthy controls using one-way Analysis of Variance with Bonferroni correction and p-values <.05 were considered significant. Receiver operating characteristic (ROC) curves were performed to assess diagnostic accuracy. Results FA of median nerve lesion fascicles was decreased compared to median nerve non-lesion fascicles, ulnar nerve and radial nerve while MD, RD, and AD was increased (p < .001 for all parameters). Compared to median nerve values of healthy controls, lesion fascicles showed a significant decrease in FA while MD, RD, and AD was increased (p < .001 for all parameters). FA of median nerve non-lesion fascicles showed a weak significant decrease compared to healthy controls (p < .01) while there was no difference in MD, RD, and AD. ROC analyses revealed an excellent diagnostic accuracy of FA, MD and RD in the discrimination of median nerve lesion and non-lesion fascicles in AINS patients as well as in the discrimination of lesion fascicles and normative median nerve values of healthy controls. Conclusion By applying this functional MR Neurography technique in patients with AINS, this proof of principle study demonstrates that diffusion tensor imaging is feasible to quantify structural nerve injury at the anatomical level of individual fascicles. KW - anterior interosseous nerve syndrome KW - diffusion tensor imaging KW - functional MR Neurography Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233061 VL - 21 ER - TY - JOUR A1 - Levitis, Elizabeth A1 - Gould van Praag, Cassandra D A1 - Gau, Rémi A1 - Heunis, Stephan A1 - DuPre, Elizabeth A1 - Kiar, Gregory A1 - Bottenhorn, Katherine L A1 - Glatard, Tristan A1 - Nikolaidis, Aki A1 - Whitaker, Kirstie Jane A1 - Mancini, Matteo A1 - Niso, Guiomar A1 - Afyouni, Soroosh A1 - Alonso-Ortiz, Eva A1 - Appelhoff, Stefan A1 - Arnatkeviciute, Aurina A1 - Atay, Selim Melvin A1 - Auer, Tibor A1 - Baracchini, Giulia A1 - Bayer, Johanna M M A1 - Beauvais, Michael J S A1 - Bijsterbosch, Janine D A1 - Bilgin, Isil P A1 - Bollmann, Saskia A1 - Bollmann, Steffen A1 - Botvinik-Nezer, Rotem A1 - Bright, Molly G A1 - Calhoun, Vince D A1 - Chen, Xiao A1 - Chopra, Sidhant A1 - Chuan-Peng, Hu A1 - Close, Thomas G A1 - Cookson, Savannah L A1 - Craddock, R Cameron A1 - De La Vega, Alejandro A1 - De Leener, Benjamin A1 - Demeter, Damion V A1 - Di Maio, Paola A1 - Dickie, Erin W A1 - Eickhoff, Simon B A1 - Esteban, Oscar A1 - Finc, Karolina A1 - Frigo, Matteo A1 - Ganesan, Saampras A1 - Ganz, Melanie A1 - Garner, Kelly G A1 - Garza-Villarreal, Eduardo A A1 - Gonzalez-Escamilla, Gabriel A1 - Goswami, Rohit A1 - Griffiths, John D A1 - Grootswagers, Tijl A1 - Guay, Samuel A1 - Guest, Olivia A1 - Handwerker, Daniel A A1 - Herholz, Peer A1 - Heuer, Katja A1 - Huijser, Dorien C A1 - Iacovella, Vittorio A1 - Joseph, Michael J E A1 - Karakuzu, Agah A1 - Keator, David B A1 - Kobeleva, Xenia A1 - Kumar, Manoj A1 - Laird, Angela R A1 - Larson-Prior, Linda J A1 - Lautarescu, Alexandra A1 - Lazari, Alberto A1 - Legarreta, Jon Haitz A1 - Li, Xue-Ying A1 - Lv, Jinglei A1 - Mansour L., Sina A1 - Meunier, David A1 - Moraczewski, Dustin A1 - Nandi, Tulika A1 - Nastase, Samuel A A1 - Nau, Matthias A1 - Noble, Stephanie A1 - Norgaard, Martin A1 - Obungoloch, Johnes A1 - Oostenveld, Robert A1 - Orchard, Edwina R A1 - Pinho, Ana Luísa A1 - Poldrack, Russell A A1 - Qiu, Anqi A1 - Raamana, Pradeep Reddy A1 - Rokem, Ariel A1 - Rutherford, Saige A1 - Sharan, Malvika A1 - Shaw, Thomas B A1 - Syeda, Warda T A1 - Testerman, Meghan M A1 - Toro, Roberto A1 - Valk, Sofie L A1 - Van Den Bossche, Sofie A1 - Varoquaux, Gaël A1 - Váša, František A1 - Veldsman, Michele A1 - Vohryzek, Jakub A1 - Wagner, Adina S A1 - Walsh, Reubs J A1 - White, Tonya A1 - Wong, Fu-Te A1 - Xie, Xihe A1 - Yan, Chao-Gan A1 - Yang, Yu-Fang A1 - Yee, Yohan A1 - Zanitti, Gaston E A1 - Van Gulick, Ana E A1 - Duff, Eugene A1 - Maumet, Camille T1 - Centering inclusivity in the design of online conferences—An OHBM–Open Science perspective JF - GigaScience N2 - As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume. KW - online conferences KW - diversity KW - inclusivity KW - open science KW - collaborative events Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371574 VL - 10 ER - TY - JOUR A1 - Liang, Huan-Chang A1 - Costanza, Mariantonia A1 - Prutsch, Nicole A1 - Zimmerman, Mark W. A1 - Gurnhofer, Elisabeth A1 - Montes-Mojarro, Ivonne A. A1 - Abraham, Brian J. A1 - Prokoph, Nina A1 - Stoiber, Stefan A1 - Tangermann, Simone A1 - Lobello, Cosimo A1 - Oppelt, Jan A1 - Anagnostopoulos, Ioannis A1 - Hielscher, Thomas A1 - Pervez, Shahid A1 - Klapper, Wolfram A1 - Zammarchi, Francesca A1 - Silva, Daniel-Adriano A1 - Garcia, K. Christopher A1 - Baker, David A1 - Janz, Martin A1 - Schleussner, Nikolai A1 - Fend, Falko A1 - Pospíšilová, Šárka A1 - Janiková, Andrea A1 - Wallwitz, Jacqueline A1 - Stoiber, Dagmar A1 - Simonitsch-Klupp, Ingrid A1 - Cerroni, Lorenzo A1 - Pileri, Stefano A1 - de Leval, Laurence A1 - Sibon, David A1 - Fataccioli, Virginie A1 - Gaulard, Philippe A1 - Assaf, Chalid A1 - Knörr, Fabian A1 - Damm-Welk, Christine A1 - Woessmann, Wilhelm A1 - Turner, Suzanne D. A1 - Look, A. Thomas A1 - Mathas, Stephan A1 - Kenner, Lukas A1 - Merkel, Olaf T1 - Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma JF - Nature Communications N2 - Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL. KW - CRISPR-Cas9 genome editing KW - high-throughput screening KW - mechanisms of disease KW - T-cell lymphoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371581 VL - 12 ER - TY - JOUR A1 - Le Provost, Gaëtane A1 - Thiele, Jan A1 - Westphal, Catrin A1 - Penone, Caterina A1 - Allan, Eric A1 - Neyret, Margot A1 - van der Plas, Fons A1 - Ayasse, Manfred A1 - Bardgett, Richard D. A1 - Birkhofer, Klaus A1 - Boch, Steffen A1 - Bonkowski, Michael A1 - Buscot, Francois A1 - Feldhaar, Heike A1 - Gaulton, Rachel A1 - Goldmann, Kezia A1 - Gossner, Martin M. A1 - Klaus, Valentin H. A1 - Kleinebecker, Till A1 - Krauss, Jochen A1 - Renner, Swen A1 - Scherreiks, Pascal A1 - Sikorski, Johannes A1 - Baulechner, Dennis A1 - Blüthgen, Nico A1 - Bolliger, Ralph A1 - Börschig, Carmen A1 - Busch, Verena A1 - Chisté, Melanie A1 - Fiore-Donno, Anna Maria A1 - Fischer, Markus A1 - Arndt, Hartmut A1 - Hoelzel, Norbert A1 - John, Katharina A1 - Jung, Kirsten A1 - Lange, Markus A1 - Marzini, Carlo A1 - Overmann, Jörg A1 - Paŝalić, Esther A1 - Perović, David J. A1 - Prati, Daniel A1 - Schäfer, Deborah A1 - Schöning, Ingo A1 - Schrumpf, Marion A1 - Sonnemann, Ilja A1 - Steffan-Dewenter, Ingolf A1 - Tschapka, Marco A1 - Türke, Manfred A1 - Vogt, Juliane A1 - Wehner, Katja A1 - Weiner, Christiane A1 - Weisser, Wolfgang A1 - Wells, Konstans A1 - Werner, Michael A1 - Wolters, Volkmar A1 - Wubet, Tesfaye A1 - Wurst, Susanne A1 - Zaitsev, Andrey S. A1 - Manning, Peter T1 - Contrasting responses of above- and belowground diversity to multiple components of land-use intensity JF - Nature Communications N2 - Land-use intensification is a major driver of biodiversity loss. However, understanding how different components of land use drive biodiversity loss requires the investigation of multiple trophic levels across spatial scales. Using data from 150 agricultural grasslands in central Europe, we assess the influence of multiple components of local- and landscape-level land use on more than 4,000 above- and belowground taxa, spanning 20 trophic groups. Plot-level land-use intensity is strongly and negatively associated with aboveground trophic groups, but positively or not associated with belowground trophic groups. Meanwhile, both above- and belowground trophic groups respond to landscape-level land use, but to different drivers: aboveground diversity of grasslands is promoted by diverse surrounding land-cover, while belowground diversity is positively related to a high permanent forest cover in the surrounding landscape. These results highlight a role of landscape-level land use in shaping belowground communities, and suggest that revised agroecosystem management strategies are needed to conserve whole-ecosystem biodiversity. KW - biodiversity KW - community ecology KW - grassland ecology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371552 VL - 12 ER - TY - JOUR A1 - Marcu, Ana A1 - Bichmann, Leon A1 - Kuchenbecker, Leon A1 - Kowalewski, Daniel Johannes A1 - Freudenmann, Lena Katharina A1 - Backert, Linus A1 - Mühlenbruch, Lena A1 - Szolek, András A1 - Lübke, Maren A1 - Wagner, Philipp A1 - Engler, Tobias A1 - Matovina, Sabine A1 - Wang, Jian A1 - Hauri-Hohl, Mathias A1 - Martin, Roland A1 - Kapolou, Konstantina A1 - Walz, Juliane Sarah A1 - Velz, Julia A1 - Moch, Holger A1 - Regli, Luca A1 - Silginer, Manuela A1 - Weller, Michael A1 - Löffler, Markus W. A1 - Erhard, Florian A1 - Schlosser, Andreas A1 - Kohlbacher, Oliver A1 - Stevanović, Stefan A1 - Rammensee, Hans-Georg A1 - Neidert, Marian Christoph T1 - HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy JF - Journal for ImmunoTherapy of Cancer N2 - Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level. Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing. Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference. Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org . Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370160 VL - 9 ER -